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Peer-reviewedCC BYToxicological Sciences

Drinking-Water 4,4′-Methylenedianiline Establishes a Longitudinally Tractable Mouse Model of Cholestatic Liver Injury

  • Takumi Iwasaka1,2
  • Katsuhisa Morita1,3
  • Iori Azuma1,2
  • Tomoka Nakagawa1,2
  • Eri Nakashima1,2
  • Tomomi Kamei4,2
  • Yuki Kato4,2
  • Hiroyuki Kusuhara1
  • Tadahaya Mizuno1
4 affiliations
  1. 1the University of Tokyo Graduate School of Pharmaceutical Sciences, , Bunkyo-ku, Tokyo, 113-0033,
  2. 2Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo, 3-0033, Japan
  3. 3Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan
  4. 4Laboratory for Drug Discovery and Development, SHIONOGI & Co.,Ltd . Toyonaka, Osaka, 561-0825,
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Abstract

Longitudinal studies of liver injury require models that can be maintained with simple administration, low procedure-related stress, and acceptable survival. Drinking-water thioacetamide (TAA-DW) is useful for this purpose, but it mainly produces centrilobular hepatocellular injury. Few drinking-water models are available for cholestatic liver injury. Here, we tested whether 4,4'-methylenedianiline (MDA), a known bile-duct-damaging hepatotoxicant, can be used to build a practical drinking-water model of cholestatic liver injury in mice. Male C57BL/6JJcl mice received MDA in drinking water for up to 28 days. A route- and administration-schedule-matched TAA-DW model was used as a reference. Drinking-water MDA (MDA-DW) caused sustained ALT elevation without observed mortality under the tested regimen. Compared with TAA-DW, MDA-DW produced stronger cholestatic biochemical features, including increased ALP, TBIL, and TCHO. Histology showed bile duct hyperplasia with degeneration, periportal/peribiliary fibrosis, and scattered focal hepatocellular necrosis. Whole-slide image analysis supported the distinct lesion distribution between MDA-DW and TAA-DW. Early time-resolved multimodal profiling showed model-specific responses: MDA-DW showed ALT elevation around Days 2-3, increased CD8-positive T cells on Day 8, and enrichment of fibrinolysis-related gene sets, whereas TAA-DW showed a sharp early injury peak and transient eosinophil increase. Impact Statement: This study expands the range of drinking-water liver injury models by providing a low-mortality MDA-DW model with cholestatic liver injury. The model offers a simple platform for time-resolved studies of liver injury progression, tissue remodeling, and model-specific inflammatory responses.

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Cite

BibTeXRIS
BibTeX
@article{iwasaka2026drinkingwater,
  title = {{Drinking-Water 4,4′-Methylenedianiline Establishes a Longitudinally Tractable Mouse Model of Cholestatic Liver Injury}},
  author = {Takumi Iwasaka and Katsuhisa Morita and Iori Azuma and Tomoka Nakagawa and Eri Nakashima and Tomomi Kamei and Yuki Kato and Hiroyuki Kusuhara and Tadahaya Mizuno},
  journal = {Toxicological Sciences},
  year = {2026},
  month = oct,
  doi = {10.1093/toxsci/kfag142},
  url = {https://doi.org/10.1093/toxsci/kfag142},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Drinking-Water 4,4′-Methylenedianiline Establishes a Longitudinally Tractable Mouse Model of Cholestatic Liver Injury
AU  - Takumi Iwasaka
AU  - Katsuhisa Morita
AU  - Iori Azuma
AU  - Tomoka Nakagawa
AU  - Eri Nakashima
AU  - Tomomi Kamei
AU  - Yuki Kato
AU  - Hiroyuki Kusuhara
AU  - Tadahaya Mizuno
PY  - 2026
DA  - 2026/10/31
JO  - Toxicological Sciences
DO  - 10.1093/toxsci/kfag142
UR  - https://doi.org/10.1093/toxsci/kfag142
AB  - Longitudinal studies of liver injury require models that can be maintained with simple administration, low procedure-related stress, and acceptable survival. Drinking-water thioacetamide (TAA-DW) is useful for this purpose, but it mainly produces centrilobular hepatocellular injury. Few drinking-water models are available for cholestatic liver injury. Here, we tested whether 4,4'-methylenedianiline (MDA), a known bile-duct-damaging hepatotoxicant, can be used to build a practical drinking-water model of cholestatic liver injury in mice. Male C57BL/6JJcl mice received MDA in drinking water for up to 28 days. A route- and administration-schedule-matched TAA-DW model was used as a reference. Drinking-water MDA (MDA-DW) caused sustained ALT elevation without observed mortality under the tested regimen. Compared with TAA-DW, MDA-DW produced stronger cholestatic biochemical features, including increased ALP, TBIL, and TCHO. Histology showed bile duct hyperplasia with degeneration, periportal/peribiliary fibrosis, and scattered focal hepatocellular necrosis. Whole-slide image analysis supported the distinct lesion distribution between MDA-DW and TAA-DW. Early time-resolved multimodal profiling showed model-specific responses: MDA-DW showed ALT elevation around Days 2-3, increased CD8-positive T cells on Day 8, and enrichment of fibrinolysis-related gene sets, whereas TAA-DW showed a sharp early injury peak and transient eosinophil increase. Impact Statement: This study expands the range of drinking-water liver injury models by providing a low-mortality MDA-DW model with cholestatic liver injury. The model offers a simple platform for time-resolved studies of liver injury progression, tissue remodeling, and model-specific inflammatory responses.
SN  - 1096-0929
SN  - 1096-6080
ER  -